This invention relates to an aqueous metal bicarbonate solution, a process of preparing the aqueous metal bicarbonate solution and a method of preventing and treating certain inflammatory diseases, degenerative diseases and viral diseases in mammals.
Generally the certain inflammatory diseases, degenerative diseases and viral diseases in mammals are those that require extracellular or intracellular acidic conditions or extracellular or intracellular proton concentrations at some point in disease process or disease pathogenesis.
Typically the certain inflammatory diseases, degenerative diseases and viral diseases in mammals are those that require the activities of carbonic anhydrase enzymes and/or the activities of acid (aspartic) protease enzymes and/or the activities of endosomal or lysosomal acid-requiring-enzymes and/or the activities of V-type ATPase proton pumps at some point in disease process or disease pathogenesis. Typically the certain inflammatory diseases, degenerative diseases and viral diseases in mammals are represented by the diseases of arthritis and influenza.
This invention relates to a method of using an aqueous metal bicarbonate solution to decrease senescence and to increase longevity in mammals. Generally senescence is decreased and longevity is increased in mammals by improving the buffering capacity of the extracellular and intracellular fluids of the body. Generally senescence is decreased and longevity is increased in mammals by the improved buffering capacity causing a decrease in proton concentrations in the extracellular and intracellular fluids of the body. Typically senescence is decreased and longevity is increased in mammals by improving the buffering capacity of the extracellular and intracellular bicarbonate buffers. Typically senescence is decreased and longevity is increased in mammals by the improved extracellular and intracellular bicarbonate buffers causing a decrease in proton concentrations.
Certain inflammatory diseases, degenerative diseases and viral diseases are major causes of morbidity and mortality in mammals. Typically these diseases are represented by the diseases of arthritis and influenza.
Arthritis is any inflammatory condition of the joints, characterised by pain and swelling. Osteoarthritis is the most common form of arthritis in which one or many joints undergo degenerative changes. Treatment includes rest of the involved joints, heat, and antiinflammatory drugs. Intraarticular injections of corticosteroids may give relief. Surgical treatment is sometimes necessary and may reduce pain and greatly improve the function of the joint. However these treatments, apart from surgical treatment, only provide temporary relief and some may have severe side reactions.
Influenza is a highly contagious infection of the respiratory tract caused by a myxovirus and transmitted by airborne droplet infection. It occurs in isolated cases, epidemics and pandemics. Treatment is symptomatic and usually involves bed rest, antipyretics such as aspirin and drinking of fluids. New strains of the virus emerge at regular intervals so it is difficult to take preventative measures to avoid the infection. There is a need for a method to prevent and to treat certain inflammatory diseases, degenerative diseases and viral diseases in mammals. There is a need for a method to prevent and to treat arthritis and influenza in mammals.
Senescence in mammals is characterised by progressive oxidations of the structural and functional molecules that constitute body cells and tissues. Oxidations of the structural and functional molecules in body cells and tissues are increased in rate by acidic conditions. Oxidations of structural and functional molecules are increased in rate by the presence of excess proton concentrations. There is a need for a method to prevent and treat excess proton concentrations in body cells so that oxidations of structural and functional molecules are decreased in rate. There is a need for a method to decrease and treat senescence in mammals.
It is an object of this invention to provide an aqueous metal bicarbonate solution to prevent and to treat certain inflammatory diseases, degenerative diseases and viral diseases in mammals. It is a further object of this invention to provide a process of preparing the aqueous metal bicarbonate solution. It is also an object of this invention to provide methods for the prevention and treatment of certain inflammatory diseases, degenerative diseases and viral diseases in mammals using the aqueous metal bicarbonate solution. Generally the certain inflammatory diseases, degenerative diseases and viral diseases in. mammals are those that require extracellular or intracellular acidic conditions or extracellular or intracellular proton concentrations at some point in disease process or disease pathogenesis. Typically the certain inflammatory diseases, degenerative diseases and viral diseases in mammals are those that require the activities of carbonic anhydrase enzymes and/or the activities of acid (aspartic) protease enzymes and/or the activities of endosomal or lysosomal acid-requiring-enzymes and/or the activities of V-type ATPase proton pumps at some point in disease process or disease pathogenesis. Typically the certain inflammatory diseases, degenerative diseases and viral diseases in mammals are represented by the diseases of arthritis and influenza.
It is an object of this invention to provide an aqueous metal bicarbonate solution to decrease senescence and to treat senescence and to increase longevity in mammals. It is a further object of this invention to provide a process of preparing the aqueous metal bicarbonate solution. It is also an object of this invention to provide methods for the decrease of senescence and the treatment of senescence and the increase in longevity in mammals using the aqueous metal bicarbonate solution. Generally senescence is decreased and longevity is increased in mammals by improving the buffering capacity of the extracellular and intracellular fluids of the body. Generally senescence is decreased and longevity is increased in mammals by the improved buffering capacity causing a decrease in proton concentrations in the extracellular and intracellular fluids of the body. Typically senescence is decreased and longevity is increased in mammals by improving the buffering capacity of the extracellular and intracellular bicarbonate buffers. Typically senescence is decreased and longevity is increased in mammals by the improved extracellular and intracellular bicarbonate buffers causing a decrease in proton concentrations.
According to a first embodiment of the present invention there is provided an aqueous metal bicarbonate solution comprising a stoichiometric concentration of bicarbonate anions and a corresponding substantially stoichiometric concentration of metal cations in association with the bicarbonate anions, the metal bicarbonate being present in a therapeutically effective amount and an acceptable carbon dioxide-containing-aqueous diluent to maintain the metal bicarbonate in the aqueous diluent.
Typically the solution is acceptable for oral administration.
In one embodiment there is provided a combination comprising the solution of the first embodiment in combination with a stabilising agent in an amount effective to maintain and stabilise the bicarbonate anions in the neutral to mildly alkaline solution. Generally the combination is kept in a sealed or closed container at 0.8 to 5 atmospheres, more typically 1 atmosphere at 0-25xc2x0 C., more typically 0.1-10xc2x0 C. In one particular embodiment the stabilising agent may be present in the solution in an amount effective to maintain and stabilise the bicarbonate anions in the neutral to mildly alkaline solution. In another particular embodiment the stabilising agent may consist of or comprise a gas above the solution in an amount effective to maintain and stabilise the bicarbonate anions in the neutral to mildly alkaline solution. In a further particular embodiment the stabilising agent may be present in the solution and also may consist of or comprise a gas above the solution, the total amount of stabilising agent in the solution and in the gas above the solution being in an amount effective to maintain and stabilise the bicarbonate anions in the neutral to mildly alkaline solution. The stabilising agent which consists of a gas above the solution may be carbon dioxide. The stabilising agent which comprises a gas above the solution may be carbon dioxide in an an inert gas such as nitrogen, air, oxygen, argon and/or helium, for example. The stabilising agent in the solution may be carbon dioxide dissolved in the solution, hydrated carbon dioxide, carbonic acid, and/or other suitable source of carbon dioxide.
According to a second embodiment of the present invention there is provided a process of preparing an aqueous metal bicarbonate solution comprising a stoichiometric concentration of bicarbonate anions and a corresponding substantially stoichiometric concentration of metal cations in association with the bicarbonate anions, which process comprises reacting a concentration of a metal carbonate or metal carbonate hydroxide or metal oxide or metal hydroxide with a concentration of carbonic acid or hydrated carbon dioxide to produce the metal bicarbonate aqueous solution, wherein said metal bicarbonate being present in a therapeutically effective amount.
Typically the aqueous metal bicarbonate solution has a neutral to mildly alkaline pH. Typically the pH is in the range 7 to 9. Typically the temperature of the aqueous metal bicarbonate solution is maintained at a level to maintain the metal bicarbonate in the aqueous diluent.
According to a third embodiment of the present invention there is provided an aqueous metal bicarbonate solution whenever prepared by the process of the second embodiment.
According to a fourth embodiment of the present invention there is provided a method of preventing and treating certain inflammatory diseases and degenerative diseases in a mammal in need of such prevention or treatment comprising administering to said mammal an effective amount of an aqueous metal bicarbonate solution of the first or third embodiment or a metal bicarbonate.
Generally the certain inflammatory diseases and degenerative diseases in a mammal are those that require extracellular or intracellular acidic conditions or extracellular or intracellular proton concentrations at some point in disease process or disease pathogenesis.
Typically the certain inflammatory diseases and degenerative diseases in a mammal are those that require the activities of carbonic anhydrase enzymes and/or the activities of acid (aspartic) protease enzymes and/or the activities of endosomal or lysosomal acid-requiring-enzymes and/or the activities of V-type ATPase proton pumps at some point in disease process or disease pathogenesis.
Typically the certain inflammatory diseases or degenerative diseases may present as arthritis. Typically the arthritis may present as osteoarthritis.
According to a fifth embodiment of the present invention there is provided a method of preventing and treating certain viral diseases in a mammal in need of such prevention or treatment comprising administering to said mammal an effective amount of an aqueous metal bicarbonate solution of the first or third embodiment or a metal bicarbonate.
Typically the certain viral diseases require intracellular acidic conditions or intracellular proton concentrations for either removal of viral protein coats or assembly of viral protein coats. Typically the viral diseases may present as influenza.
According to a sixth embodiment of the present invention there is provided a method of decreasing and treating senescence and of increasing longevity in a mammal comprising administering to said mammal an effective amount of an aqueous metal bicarbonate solution of the first or third embodiment or a metal bicarbonate.
Typically senescence is decreased and longevity is increased by maintaining or increasing normal extracellular and/or intracellular alkaline conditions. Typically senescence is decreased and longevity is increased by improving the buffering capacity of the extracellular and intracellular fluids of the body. Typically longevity is increased by maintaining or increasing normal mitochondrial alkaline conditions. Typically longevity is increased by decreasing extracellular and intracellular acidic conditions or by decreasing extracellular and intracellular proton concentrations.
Typically senescence is decreased and longevity is increased in mammals by improving the buffering capacity of the extracellular and intracellular bicarbonate buffers. Typically senescence is decreased and longevity is increased in mammals by the improved extracellular and intracellular bicarbonate buffers causing a decrease in proton concentrations. Typically senescence is decreased and longevity is increased by preventing or treating certain inflammatory diseases, degenerative diseases and viral diseases in mammals. Typically longevity is increased by decreasing the morbidity and mortality associated with these diseases.
According to a seventh embodiment of the present invention there is provided a method of scavenging protons in a mammal comprising administering to said mammal an effective amount of a proton scavenger.
Typically the proton scavenger comprises a metal bicarbonate. Typically the metal bicarbonate is in the form of the aqueous metal bicarbonate solution of the first or third embodiment.
According to an eighth embodiment of the present invention there is provided a method of decreasing proton concentrations in a mammal by altering carbonic anhydrase enzyme reactions in said mammal comprising administering to said mammal an effective amount of an aqueous metal bicarbonate solution of the first or third embodiment or a metal bicarbonate.
According to a ninth embodiment of the present invention there is provided a method of decreasing inflammation and inflammatory conditions in a mammal comprising administering to said mammal an effective amount of an aqueous metal bicarbonate solution of the first or third embodiment or a metal bicarbonate.
Generally inflammation and inflammatory conditions are decreased by decreasing the extracellular and intracellular acidic conditions that are required for inflammatory processes. Generally inflammation and inflammatory conditions are decreased by decreasing the extracellular and intracellular proton concentrations that are required for inflammatory processes. Typically inflammation is decreased by altering carbonic anhydrase enzyme reactions and/or decreasing the activities of acid (aspartic) protease enzymes and/or decreasing the activities of endosomal or lysosomal acid-requiring-enzymes and/or decreasing the activities of V-type ATPase proton pumps.
According to a tenth embodiment of the present invention there is provided a method of increasing motor activity in a mammal comprising administering to said mammal an effective amount of an aqueous metal bicarbonate solution of the first or third embodiment or a metal bicarbonate.
Typically motor activity is increased by decreasing extracellular and intracellular acidic conditions or by decreasing extracellular and intracellular proton concentrations. Typically motor activity is increased by improving the buffering capacity of extracellular and intracellular fluids. Typically motor activity is increased by improving the buffering capacity of the extracellular and intracellular bicarbonate buffers. Typically motor activity is increased by increasing extracellular and intracellular alkaline conditions. Typically motor activity is increased by scavenging protons produced by ATP hydrolysis, lactic acid production, lipid metabolism and other metabolic processes.
According to an eleventh embodiment of the present invention there is provided an aqueous neutral to mildly alkaline metal bicarbonate solution, comprising metal bicarbonate dissolved in the solution, said metal bicarbonate comprising bicarbonate anions and metal cations, and a pH adjusting agent in the solution in an amount whereby the solution is at a neutral to mildly alkaline pH.
Typically a corresponding substantially stoichiometric concentration of metal cations are in association with the bicarbonate anions. Typically the solution is acceptable for oral administration.
In one embodiment there is provided a combination comprising a substantially stable aqueous neutral to mildly alkaline metal bicarbonate solution, comprising metal bicarbonate dissolved in the solution, said metal bicarbonate comprising bicarbonate anions and metal cations, and a pH adjusting agent in the solution in an amount whereby the solution is at a neutral to mildly alkaline pH, in combination with a stabilising agent in an amount effective to maintain and stabilise the bicarbonate anions in the neutral to mildly alkaline solution. In another embodiment there is provided a combination comprising a substantially stable aqueous neutral to mildly alkaline metal bicarbonate solution, comprising metal bicarbonate dissolved in the solution, said metal bicarbonate comprising bicarbonate anions and metal cations, in combination with a stabilising agent in an amount effective to maintain and stabilise the bicarbonate anions in the solution whereby the solution is at a neutral to mildly alkaline pH.
The pH adjusting agent and the stabilising agent may be the same or different. Generally the combination is kept in a sealed or closed container at 0.8 to 5 atmospheres, more typically 1 atmosphere at 0-25xc2x0 C., more typically 0.1-10xc2x0 C.
In one particular embodiment the stabilising agent may be present in the solution in an amount effective to maintain and stabilise the bicarbonate anions in the neutral to mildly alkaline solution. In another particular embodiment the stabilising agent may consist of or comprise a gas above the solution in an amount effective to maintain and stabilise the bicarbonate anions in the neutral to mildly alkaline solution. In a further particular embodiment the stabilising agent may be present in the solution and may consist of or comprise a gas above the solution, the total amount of stabilising agent in the solution and in the gas above the solution being in an amount effective to maintain and stabilise the bicarbonate anions in the neutral to mildly alkaline solution. The stabilising agent which consists of a gas above the solution may be carbon dioxide. The stabilising agent which comprises a gas above the solution may be carbon dioxide in an an inert gas such as nitrogen, air, oxygen, argon and/or helium, for example. The stabilising agent in the solution may be carbon dioxide dissolved in the solution, hydrated carbon dioxide, carbonic acid, and/or other suitable source of carbon dioxide.
According to a twelfth embodiment of the present invention there is provided a solution for preventing and/or treating certain inflammatory diseases and/or degenerative diseases and/or certain viral diseases in a mammal, comprising the aqueous neutral to mildly alkaline metal bicarbonate solution of the eleventh embodiment whereby the metal bicarbonate is present in an amount effective to prevent and/or treat said diseases.
According to a thirteenth embodiment of the present invention there is provided a solution for decreasing and/or treating senescence and/or increasing longevity in a mammal, comprising the aqueous neutral to mildly alkaline metal bicarbonate solution of the eleventh embodiment whereby the metal bicarbonate is present in an amount effective to decrease and/or treat senescence and/or increase longevity.
According to a fourteenth embodiment of the present invention there is provided a solution for scavenging protons in a mammal, comprising the aqueous neutral to mildly alkaline metal bicarbonate solution of the eleventh embodiment whereby the metal bicarbonate is present in an amount effective to scavenge protons.
According to a fifteenth embodiment of the present invention there is provided a solution for decreasing proton concentrations in a mammal, comprising the aqueous neutral to mildly alkaline metal bicarbonate solution of the eleventh embodiment whereby the metal bicarbonate is present in an amount effective to decrease proton concentrations.
According to a sixteenth embodiment of the present invention there is provided a solution for decreasing inflammation and inflammatory conditions in a mammal, comprising the aqueous neutral to mildly alkaline metal bicarbonate solution of the eleventh embodiment whereby the metal bicarbonate is present in an amount effective to decrease inflammation and/or inflammatory conditions.
According to a seventeenth embodiment of the present invention there is provided a solution for increasing motor activity and/or decrease fatigue in a mammal, comprising the aqueous neutral to mildly alkaline metal bicarbonate solution of the eleventh embodiment whereby the metal bicarbonate is present in an amount effective to increase motor activity.
According to an eighteenth embodiment of the present invention there is provided a process of preparing an aqueous neutral to mildly alkaline metal bicarbonate solution comprising bicarbonate anions and metal cations, which process comprises reacting a compound selected from the group consisting of metal carbonate, metal carbonate hydroxide, metal oxide, metal hydroxide and any mixture thereof with an effective concentration of a pH adjusting agent to produce the aqueous neutral to mildly alkaline metal bicarbonate solution, wherein the pH adjusting agent is present in an amount whereby the solution is at a neutral to mildly alkaline pH.
Typically a corresponding substantially stoichiometric concentration of metal cations are in association with the bicarbonate anions. Generally the solution is stored in a sealed or closed container at 0.8 to 5 atmospheres, more typically 1 atmosphere at 0-25xc2x0 C., more typically 0.1-10xc2x0 C. In one embodiment the process further comprises combining the solution with a stabilising agent in an amount effective to maintain and stabilise the bicarbonate anions in the neutral to mildly alkaline solution. In one particular embodiment the process comprises conducting the process under gaseous atmosphere comprising a stabilising agent in an amount effective to maintain and stabilise the bicarbonate anions in the neutral to mildly alkaline solution. The stabilising agent may be carbon dioxide or comprise carbon dioxide in an inert gas such as nitrogen, air, oxygen, argon and/or helium, for example. Generally the combination is stored in a sealed or closed container at 0.8 to 5 atmospheres, more typically 1 atmosphere at 0-25xc2x0 C., more typically 0.1-10xc2x0 C.
One particular embodiment may comprise adding the stabilising agent to the solution in the solution in an amount effective to maintain and stabilise the bicarbonate anions in the neutral to mildly alkaline solution. Another particular embodiment may comprise blanketing the solution with a gas consisting of or comprising the stabilising agent in an amount effective to maintain and stabilise the bicarbonate anions in the neutral to mildly alkaline solution. A further particular embodiment may comprise adding the stabilising agent to the solution in the solution and blanketing the solution with a gas consisting of or comprising the stabilising agent, the total amount of stabilising agent in the solution and in the gas above the solution being in an amount effective to maintain and stabilise the bicarbonate anions in the neutral to mildly alkaline solution. The stabilising agent which consists of a gas above the solution may be carbon dioxide. The stabilising agent which comprises a gas above the solution may be carbon dioxide in an inert gas such as nitrogen, air, oxygen, argon and/or helium, for example. The stabilising agent in the solution may be carbon dioxide dissolved in the solution, hydrated carbon dioxide, carbonic acid, and/or other suitable source of carbon dioxide.
According to a nineteenth embodiment of the present invention there is provided a aqueous neutral to mildly alkaline metal bicarbonate solution whenever prepared by the process of the eighteenth embodiment.
According to a twentieth embodiment of the present invention there is provided a method of preventing and/or treating certain inflammatory diseases and/or degenerative diseases in a mammal in need of such prevention and/or treatment comprising administering to said mammal an effective amount of an aqueous neutral to mildly alkaline metal bicarbonate solution of the eleventh or a metal bicarbonate.
Generally the certain inflammatory diseases and degenerative diseases in a mammal are those that require extracellular or intracellular acidic conditions or extracellular or intracellular proton concentrations at some point in disease process or disease pathogenesis.
Typically the certain inflammatory diseases and degenerative diseases in a mammal are those that require the activities of carbonic anhydrase enzymes and/or the activities of acid (aspartic) protease enzymes and/or the activities of endosomal or lysosomal acid-requiring-enzymes and/or the activities of V-type ATPase proton pumps at some point in disease process or disease pathogenesis.
Typically the certain inflammatory diseases or degenerative diseases may present as arthritis. Typically the arthritis may present as osteoarthritis.
According to a twenty-first embodiment of the present invention there is provided a method of preventing and/or treating certain viral diseases in a mammal in need of such prevention and/or treatment comprising administering to said mammal an effective amount of an aqueous neutral to mildly alkaline metal bicarbonate solution of the eleventh embodiment or a metal bicarbonate.
Typically the certain viral diseases require intracellular acidic conditions or intracellular proton concentrations for either removal of viral protein coats or assembly of viral protein coats. Typically the viral diseases may present as influenza.
According to a twenty-second embodiment of the present invention there is provided a method of decreasing and/or treating senescence and/or of increasing longevity in a mammal comprising administering to said mammal an effective amount of an aqueous neutral to mildly alkaline metal bicarbonate solution of the eleventh embodiment or a metal bicarbonate.
Typically senescence is decreased and longevity is increased by maintaining or increasing normal extracellular and/or intracellular alkaline conditions. Typically senescence is decreased and longevity is increased by improving the buffering capacity of the extracellular and intracellular fluids of the body. Typically longevity is increased by maintaining or increasing normal mitochondrial alkaline conditions. Typically longevity is increased by decreasing extracellular and intracellular acidic conditions or by decreasing extracellular and intracellular proton concentrations. Typically senescence is decreased and longevity is increased in mammals by improving the buffering capacity of the extracellular and intracellular bicarbonate buffers. Typically senescence is decreased and longevity is increased in mammals by the improved extracellular and intracellular bicarbonate buffers causing a decrease in proton concentrations.
Typically senescence is decreased and longevity is increased by preventing or treating certain inflammatory diseases, degenerative diseases and viral diseases in mammals. Typically longevity is increased by decreasing the morbidity and mortality associated with these diseases.
According to a twenty-third embodiment of the present invention there is provided a method of scavenging protons in a mammal comprising administering to said mammal an effective amount of a proton scavenger.
Typically the proton scavenger comprises a metal bicarbonate. Typically the metal bicarbonate is in the form of the aqueous neutral to mildly alkaline metal bicarbonate solution of the eleventh embodiment.
According to a twenty-fourth embodiment of the present invention there is provided a method of decreasing proton concentrations in a mammal by altering carbonic anhydrase enzyme reactions in said mammal comprising administering to said mammal an effective amount of an aqueous neutral to mildly alkaline metal bicarbonate solution of the eleventh embodiment or a metal bicarbonate.
According to a twenty-fifth embodiment of the present invention there is provided a method of decreasing inflammation and/or inflammatory conditions in a mammal comprising administering to said mammal an effective amount of an aqueous neutral to mildly alkaline metal bicarbonate solution of the eleventh embodiment or a metal bicarbonate.
Generally inflammation and inflammatory conditions are decreased by decreasing the extracellular and intracellular acidic conditions that are required for inflammatory processes. Generally inflammation and inflammatory conditions are decreased by decreasing the extracellular and intracellular proton concentrations that are required for inflammatory processes. Typically inflammation is decreased by altering carbonic anhydrase enzyme reactions and/or decreasing the activities of acid (aspartic) protease enzymes and/or decreasing the activities of endosomal or lysosoinal acid-requiring-enzymes and/or decreasing the activities of V-type ATPase proton pumps.
According to a twenty-sixth embodiment of the present invention there is provided a method of increasing motor activity and/or decreasing fatigue in a mammal comprising administering to said mammal an effective amount of an aqueous neutral to mildly alkaline metal bicarbonate solution of the eleventh embodiment or a metal bicarbonate.
The methods of the invention typically involve orally administering to the mammal, the mammal being typically human. Further the methods of the invention typically involve orally administering to a mammal in need of treatment for the specified condition of the particular embodiment, the mammal being typically human. Typically motor activity is increased by decreasing extracellular and intracellular acidic conditions or by decreasing extracellular and intracellular proton concentrations. Typically motor activity is increased by improving the buffering capacity of extracellular and intracellular fluids. Typically motor activity is increased by improving the buffering capacity of the extracellular and intracellular bicarbonate buffers. Typically motor activity is increased by increasing extracellular and intracellular alkaline conditions. Typically motor activity is increased by scavenging protons produced by ATP hydrolysis, lactic acid production, lipid metabolism and other metabolic processes.
The term mammal as used herein includes vertebrate. Examples of mammals and vertebrates to which the methods of the invention apply include a bovine, human (male or female), ovine, equine, caprine, Leporine, feline or canine mammal or vertebrate. Specific examples of animals include sheep, cattle, horses, rabbits, cats, goats, alpacas, cats, dogs, pigs, rabbits, fowls, deer, buffaloes and other livestock and domestic animals.
Metal Bicarbonate Generally
Generally the pH of the aqueous metal bicarbonate solution is neutral to mildly alkaline, typically mildly alkaline and more typically in the range of 7 to 9 even more typically 8 to 8.6 and the temperature of the aqueous neutral to mildly alkaline metal bicarbonate solution is maintained at such a level so as to maintain the metal bicarbonate in the aqueous diluent. The aqueous neutral to mildly alkaline metal bicarbonate solution may be kept under an atmosphere comprising carbon dioxide of from about 0.8 to 5 or 1 to 5 atmospheres, more typically 1 to 3 atmospheres and even more typically slightly above atmospheric pressure such as the sorts of pressures that soft drinks are currently under in cans or bottles, for example, so as to maintain the metal bicarbonate in the aqueous diluent.
Generally the metal cation is an alkaline earth metal cation or an alkali metal cation. Generally a metal cation is chosen which is capable of acting as a bicarbonate transporter into mammalian cells. More particularly the metal cation may be cations of magnesium, sodium, potassium, calcium, lithium or any mixture thereof. Where a mixture of alkaline earth metal cations or alkali metal cations are used: (1) two different alkaline earth metal cations or alkali metal cations or mixtures thereof, the molar ratio of the first metal cation to the second may be in the range 0.5:99.5 to 99.5:0.5, typically 75:25 to 25:75, more typically 0.7:1 to 1:0.7; (2) three different alkaline earth metal cations or alkali metal cations or mixtures thereof, the molar ratio of the first metal cation to the second to the third may be in the range 99.5:0.5:0.5 to 0.5:99.5:99.5, typically 75:25:25 to 25:75:75, more typically 0.5:1:1 to 1:0.5:0.5; (3) four different alkaline earth metal cations or alkali metal cations or mixtures thereof, the molar ratio of the first metal cation to the second to the third to the fourth may be in the range 99.5:0.5:0.5:0.5 to 0.5:99.5:99.5:99.5, typically 75:25:25:25 to 25:75:75:75, more typically 0.5:1:1:1 to 0.5:1:1:1. Generally the metal cation is magnesium or a mixture of magnesium and sodium metal cations. Typically the aqueous neutral to mildly alkaline metal bicarbonate solution has a high metal cation concentration in association with bicarbonate anions.
Typically the metal bicarbonate is used at a concentration of 10-100 mole% or weight% of its saturation solubility (which will depend on the actual metal bicarbonate(s) used), more typically 10-90%, 10-80%, 10-70%, 10-60%, 10-50%, 10-40%, 10-30%, 10-20%, more typically 15-95%, 15-85%, 15-75%, 15-65%, 15-55%, 15-45%, 15-35%, 15-25%, more typically 15-90%, 15-80%, 15-70%, 15-60%, 15-50%, 15-40%, 15-30%, 15-20%, more typically 10-95%, 10-85%, 10-75%, 10-65%, 10-55%, 10-45%, 10-35%, 10-25%, more typically 20-90%, 20-80%, 20-70%, 20-60%, 20-50%, 20-40%, 20-30%, more typically 25-95%, 25-85%, 25-75%, 25-65%, 25-55%, 25-45%, 25-35%, more typically 25-90%, 25-80%, 25-70%, 25-60%, 25-50%, 25-40%, 25-30%, more typically 20-95%, 20-85%, 20-75%, 20-65%, 20-55%, 2045%, 20-35%, more typically 30-90%, 30-80%, 30-70%, 30-60%, 30-50%, 3040%, more typically 35-95%, 35-85%, 35-75%, 35-65%, 35-55%, 35-45%, more typically 35-90%, 35-80%, 35-70%, 35-60%, 35-50%, 35-40%, more typically 30-95%, 30-85%, 30-75 %, 30-65%, 30-55%, 3045%, more typically 40-90%, 40-80%, 40-70%, 40-60%, 40-50%, more typically 45-95%, 45-85%, 45-75%, 45-65 %, 45-55%, more typically 45-90%, 45-80%, 45-70%, 45-60%, 45-50%, more typically 40-95%, 40-85%, 40-75 %, 40-65%, 40-55%, more typically 50-90%, 50-80%, 50-70%, 50-60%, more typically 55-95%, 55-85%, 55-75%, 55-65%, more typically 55-90%, 55-80%, 55-70%, 55-60%, more typically 50-95%, 50-85%, 50-75%, 50-65%, more typically 60-90%, 60-80%, 60-70%, more typically 65-95%, 65-85%, 65-75%, more typically 65-90%, 65-80%, 65-70%, more typically 60-95%, 60-85%, 60-75%, more typically 70-90%, 70-80%, more typically 75-95%, 75-85%, more typically 75-90%, 75-80%, more typically 70-95%, 70-85%, more typically 80-90%, more typically 85-95%, more typically 85-90%, more typically 80-95%, more typically 20-100%, 30-100%, 40-100%, 50-100%, 60-100%, 70-100%, 80-100% or 90-100%. Depending on the solubility of the metal bicarbonate, the amount of metal cation may range from 20 mg to 1250 mg or 25 mg to 1250 mg per liter of aqueous neutral to mildly alkaline metal bicarbonate solution, typically 20 mg to 1000 mg or 50 mg to 1000 mg per liter of aqueous neutral to mildly alkaline metal bicarbonate solution, more typically 20mg to 750mg or 50 mg to 750 mg or 20 mg to 600 mg or 50 mg to 600 mg per liter of aqueous neutral to mildly alkaline metal bicarbonate solution, even more typically 20 mg to 500 mg or 30 mg to 500 mg or 50 mg to 500 mg per liter of aqueous neutral to mildly alkaline metal bicarbonate solution, even more typically 20 mg to 250 mg or 50 mg to 250 mg per liter of aqueous neutral to mildly alkaline metal bicarbonate solution, most typically 100 mg to 500 mg or 100 mg to 400 mg or 100 mg to 300 mg or 100 mg to 250 mg per liter of aqueous neutral to mildly alkaline metal bicarbonate solution, even most typically 20 mg to 200 mg or 20 to 150 mg or 20 mg to 120 mg or 120 mg to 300 mg or 120 mg to 200 mg. Typically when the metal cation is magnesium, the amount of magnesium may range from 30 mg to 140 mg per liter of aqueous neutral to mildly alkaline metal bicarbonate solution, typically 30 mg to 130 mg, 30 mg to 120 mg, 30 mg to 110 mg, 30 mg to 100 mg, 30 mg to 90 mg, 30 mg to 80 mg, 30 mg to 70 mg, 30 mg to 60 mg, 30 mg to 50 mg, 30 mg to 40 mg, 50 mg to 120 mg, 60 mg to 120 mg, 70 mg to 120 mg, 80 mg to 120 mg, 90 mg to 120 mg or 75 mg to 120 mg or 100 mg to 120 mg per liter of aqueous neutral to mildly alkaline metal bicarbonate solution. Typically when the metal cation is sodium and/or potassium, the amount of sodium and/or potassium may range from greater than 30 mg to 1250 mg per liter of aqueous neutral to mildly alkaline metal bicarbonate solution, typically 50 mg to 1000 mg or 50 mg to 750 mg or 50 mg to 500 mg or 75 mg to 1250 mg or 75 mg to 1000 mg or 75 mg to 500 mg or 100 mg to 1000 mg or 100 mg to 500 mg or 250 mg to 1000 mg or 250 mg to 500 mg per liter of aqueous neutral to mildly alkaline metal bicarbonate solution. Typically when the metal cation is calcium, the amount of calcium may range from greater than 20mg to 1250 mg per liter of aqueous neutral to mildly alkaline metal bicarbonate solution, typically 20 mg to 1000 mg or 20 mg to 750 mg or 20 mg to 500 mg or 20 mg to 250 mg or 20 mg to 200 mg or 20 mg to 150 mg or 20 mg to 100 mg per liter of aqueous neutral to mildly alkaline metal bicarbonate solution. Typically the amount of bicarbonate anion present will be stoichiometric with the amount of metal cation in solution so as to form the metal bicarbonate. Alternatively, the concentration of the metal bicarbonate can be based on the bicarbonate anion concentrations in which case the amount of bicarbonate anion (which will depend on the saturation solubility of the actual metal bicarbonate anion(s) used). The concentration of bicarbonate typically ranges from 120 mg or 150 mg to 3500 mg per liter of aqueous neutral to mildly alkaline metal bicarbonate solution, typically 120 mg or 150 mg to 3000 mg or 200 mg to 3000 mg per liter of aqueous neutral to mildly alkaline metal bicarbonate solution, more typically 250 mg to 2100 mg or 300 mg to 2000 mg or 200 mg to 1500 mg or 300 mg to 1500 mg or 400 mg to 1500 mg or 500 mg to 1500 mg or 600 mg to 1500 mg or 700 mg to 1500 mg or 800 mg to 1500 mg or 900 mg to 1500 mg or 1000 mg to 1500 mg or 200 mg to 1000 mg or 300 mg to 1000 mg or 400 mg to 1000 mg or 500 mg to 1000 mg or 600 mg to 1000 mg or 700 mg to 1000 mg or 800 mg to 1000 mg or 900 mg to 1000 mg or 1000 mg to 1500 mg or 1200 mg to 1500 mg per liter of aqueous neutral to mildly alkaline metal bicarbonate solution, even more typically 600 mg to 1000 mg or 500 mg to 1500 mg per liter of aqueous neutral to mildly aLkaline metal bicarbonate solution, most typically 950 mg or 200 mg to 2000 mg or 200 mg to 1750 mg or 200 mg to 1250 mg or 200 mg to 100 mg per liter of aqueous neutral to mildly alkaline metal bicarbonate solution. Typically at least 600 mg of bicarbonate anions per liter of solution is present, more typically 600-1800 mg/l, 600-1500 mg/l, 600-1350 mg/1, 600-1200 mg,/l 600-1100 mg/l, 600-1000 mg/l, 600-950 mg/l, 600-900 mg/l, 600-850 mg/l, 600-800 mg/l, 600-750 mg/l, 600-700 mg/l or 600-650 mg/l. Typically a mildly alkaline saturated magnesium bicarbonate solution is used or a mildly alkaline solution comprising a mixture of sodium and/or potassium and magnesium bicarbonate, more typically sodium and magnesium bicarbonate. Typically the range for a mixture of sodium and/or potassium and magnesium bicarbonate, more typically sodium and magnesium bicarbonate varies from 20 mg to 1250 mg or 25 mg to 1250 mg per liter of aqueous neutral to mildly alkaline metal bicarbonate solution, typically 20 mg to 100 mg or 50 mg to 1000 mg per liter of aqueous neutral to mildly alkaline metal bicarbonate solution, more typically 20 mg to 750 mg or 50 mg to 750 mg or 20 mg to 600 mg or 50 mg to 600 mg per liter of aqueous neutral to mildly alkaline metal bicarbonate solution, even more typically 20 mg to 500 mg or 30 mg to 500 mg or 50 mg to 500 mg per liter of aqueous neutral to mildly alkaline metal bicarbonate solution, even more typically 20 mg to 250 mg or 50 mg to 250 mg or even more typically 20 mg to 300 mg or 50 mg to 300 mg per liter of aqueous neutral to mildly alkaline metal bicarbonate solution, most typically 75 mg to 1000 mg or 75 mg to 500 mg or 100 mg to 1000 mg or 100 mg to 500 mg or 100 mg to 400 mg or 100 mg to 300 mg or 100 mg to 250 mg per liter of aqueous neutral to mildly alkaline metal bicarbonate solution, even most typically 20 mg to 200 mg or 20 to 150 mg or 20 mg to 120 mg or 120 mg to 300 mg or 120 mg to 200 mg. Usually the ratio (weight to weight) of magnesium to sodium is in the range 25:1 to 1:4, typically 1:1.125.
Generally the aqueous diluent is water or comprises water. Generally the carbon dioxide-containing-aqueous diluent may be carbonic acid in water, hydrated carbon dioxide in water, carbon dioxide gas dissolved in water, carbonated soft drinks, carbonated mineral water, soda water or other carbon dioxide-containing-aqueous diluents. If carbon dioxide gas is used, the carbon dioxide may be either bubbled into aqueous solutions containing metal carbonate or metal carbonate hydroxide or metal oxide or mixture thereof or the carbon dioxide may be introduced in the form of a blanket over aqueous solutions containing metal carbonate or metal carbonate hydroxide or metal oxide or mixture thereof. Typically the carbon dioxide-containing-aqueous diluent is pharmaceutically acceptable. Typically carbonated mineral water, carbonic acid, hydrated carbon dioxide in water or carbonated water is used. The amounts of carbon dioxide-containing-aqueous diluent and metal carbonate or metal carbonate hydroxide or metal oxide or mixture thereof used are sufficient to obtain a clear solution at a neutral to mildly alkaline pH, typically pH 7 to 9 or pH 7 to 8.6, more typically pH 7.5 to 8.8 or pH 7.5 to 8.5 or pH 7.8 to 8.6, pH 7.8 to 8.5, pH 7.8 to 8.4, pH 7.8 to 8.3, pH 7.8 to 8.2, pH 7.8 to 8.1, pH 7.8 to 8.0, pH 7.8 to 7.9, pH 7.9 to 8.6, pH 7.9 to 8.5, pH 7.9 to 8.4, pH 7.9 to 8.3, pH 7.9 to 8.2, pH 7.9 to 8.1, pH 7.9 to 8.0, pH 8.0 to 8.6, pH 8.0 to 8.5, pH 8.0 to 8.4, pH 8.0 to 8.3, pH 8.0 to 8.2, pH 8.0 to 8.1, pH 8.1 to 8.6, pH 8.1 to 8.5, pH 8.1 to 8.4, pH 8.1 to 8.3, pH 8.1 to 8.2, pH 8.2 to 8.6, pH 8.2 to 8.5, pH 8.2 to 8.4, pH 8.2 to 8.3, pH 8.3 to 8.6, pH 8.3 to 8.5, pH 8.3 to 8.4, pH 8.4 to 8.6, pH 8.4 to 8.5, pH 8.5 to 8.6, even more typically pH 8 to 8.5 or pH 8.2 to 8.6, most typically pH 8.3. Usually 10 to 60 mL, typically 25 to 55mL, more typically 40 to 50 mL, most typically approximately 45 mL of chilled carbonated mineral water per liter of water is used. Usually the chilled carbonated mineral water is at a temperature of 0 to 25xc2x0 C., 0 to 20xc2x0 C., 0.5 to 25xc2x0 C., 0.5 to 20xc2x0 C., 0.5 to 15xc2x0 C., 0.5 to 10xc2x0 C., 0.5 to 9xc2x0 C., 0.5 to 8xc2x0 C., 0.5 to 7xc2x0 C., 1 to 20xc2x0 C., 1 to 15xc2x0 C., 1 to 10xc2x0 C., 1.5 to 20xc2x0 C., 1.5 to 15xc2x0 C., 1.5 to 10xc2x0 C., 2 to 20xc2x0 C., 2 to 15xc2x0 C., 2 to 10xc2x0 C., 3 to 20xc2x0 C., 3 to 15xc2x0 C., 4 to 20xc2x0 C., 4 to 15xc2x0 C., 4 to 10xc2x0 C., 5 to 20xc2x0 C., 5 to 15xc2x0 C., 6 to 20xc2x0 C., 6 to 15xc2x0 C., 6 to 10xc2x0 C., 7 to 20xc2x0 C., 7 to 15xc2x0 C., 7 to 10xc2x0 C., 8 to 20xc2x0 C., 8 to 15xc2x0 C., 8 to 10xc2x0 C., 9 to 20xc2x0 C., 9 to 15xc2x0 C., 9 to 10xc2x0 C., 10 to 15xc2x0 C., typically 0 to 15xc2x0 C., more typically 0 to 10xc2x0 C., even more typically 3xc2x0 C. to 10xc2x0 C., most typically 5xc2x0 C. to 10xc2x0 C. and even most typically 5xc2x0 C. Alternatively the metal carbonate or metal carbonate hydroxide or metal oxide or mixture thereof can be added after the carbon dioxide has been added.
Generally the metal bicarbonate in aqueous solution may be derived from a metal carbonate or metal carbonate hydroxide or metal oxide or metal bicarbonate or metal hydroxide or other appropriate metal compound or any mixture thereof. Examples include magnesium, sodium, potassium, calcium, lithium carbonate or carbonate hydroxide or oxide or bicarbonate or a mixture of any two or more thereof. For example magnesium carbonate hydroxide pentahydrate, the calcite series or dolomite series of minerals (Mg, Ca)CO3 or limestone or dolomite rocks is used. Generally magnesium carbonate hydroxide pentahydrate or a mixture of magnesium carbonate hydroxide pentahydrate and sodium bicarbonate is used.
Generally the pH of the aqueous metal bicarbonate solution for oral administration is neutral to mildly alkaline, typically in the range pH 7 to 9 or pH 7 to 8.6, more typically pH 7.5 to 8.8 or pH 7.5 to 8.5 or pH 7.8 to 8.6, pH 7.8 to 8.5, pH 7.8 to 8.4, pH 7.8 to 8.3, pH 7.8 to 8.2, pH 7.8 to 8.1, pH 7.8 to 8.0, pH 7.8 to 7.9, pH 7.9 to 8.6, pH 7.9 to 8.5, pH 7.9 to 8.4, pH 7.9 to 8.3, pH 7.9 to 8.2, pH 7.9 to 8.1, pH 7.9 to 8.0, pH 8.0 to 8.6, pH 8.0 to 8.5, pH 8.0 to 8.4, pH 8.0 to 8.3, pH 8.0 to 8.2, pH 8.0 to 8.1, pH 8.1 to 8.6, pH 8.1 to 8.5, pH 8.0 to 8.4, pH 8.1 to 8.3, pH 8.1 to 8.2, pH 8.2 to 8.6, pH 8.2 to 8.5, pH 8.2 to 8.4, pH 8.2 to 8.3, pH 8.3 to 8.6, pH 8.3 to 8.5, pH 8.3 to 8.4, pH 8.4 to 8.6, pH 8.4 to 8.5, pH 8.5 to 8.6, even more typically pH 8 to 8.5 or pH 8.2 to 8.6, most typically pH 8.3. Generally the pH of the aqueous metal bicarbonate solution for parenteral administration is neutral to very mildly alkaline, typically in the range pH 7 to 7.6, or pH 7.0 to 7.5, or pH 7.1 to 7.5, more typically pH 7.2 to 7.5 or pH 7.3 to 7.5 or pH 7.4 to 7.5. Generally the aqueous neutral to mildly alkaline metal bicarbonate solution is prepared and stored at a temperature ranging from 0 to 25xc2x0 C., 0 to 20xc2x0 C., 0.5 to 25xc2x0 C., 0.5 to 20xc2x0 C., 0.5 to 15xc2x0 C., 0.5 to 10xc2x0 C., 0.5 to 9xc2x0 C., 0.5 to 8xc2x0 C., 0.5 to 7xc2x0 C., 1 to 20xc2x0 C., 1 to 15xc2x0 C., 1 to 10xc2x0 C., 1.5 to 20xc2x0 C., 1.5 to 15xc2x0 C., 1.5 to 10xc2x0 C., 2 to 20xc2x0 C., 2 to 15xc2x0 C., 2 to 10xc2x0 C., 3 to 20xc2x0 C., 3 to 15xc2x0 C., 4 to 20xc2x0 C., 4 to 15xc2x0 C., 4 to 10xc2x0 C., 5 to 20xc2x0 C., 5 to 15xc2x0 C., 6 to 20xc2x0 C., 6 to 15xc2x0 C., 6 to 10xc2x0 C., 7 to 20xc2x0 C., 7 to 15xc2x0 C., 7 to 10xc2x0 C., 8 to 20xc2x0 C., 8 to 15xc2x0 C., 8 to 10xc2x0 C., 9 to 20xc2x0 C., 9 to 15xc2x0 C., 9 to 10xc2x0 C., 10 to 15xc2x0 C., typically 0 to 15xc2x0 C., more typically 0 to 10xc2x0 C., even more typically 3xc2x0 C. to 10xc2x0 C., most typically 5xc2x0 C. to 10xc2x0 C. and even most typically 5xc2x0 C.
Generally the pH adjusting agent is carbon dioxide gas, carbonic acid in water, hydrated carbon dioxide in water, carbon dioxide gas in water, carbonated soft drinks, carbonated mineral water, soda water or other carbon dioxide-containing-aqueous diluents or an alkali or any mixture thereof. Examples of alkalis are water soluble drinkable alkalis such as sodium hydroxide, sodium carbonate, potassium carbonate or potassium hydroxide or any mixture thereof.
Typically additives may be added during the process of the invention or to the aqueous neutral to mildly alkaline metal bicarbonate solution. The additives may be 0 mg or 0.5 mg to 1000 mg sodium bicarbonate per liter of aqueous neutral to mildly alkaline metal bicarbonate solution, typically 25 mg to 900 mg per liter of aqueous neutral to mildly alkaline metal bicarbonate solution, typically 50 mg to 800 mg or 50 mg to 500 mg per liter of aqueous neutral to mildly alkaline metal bicarbonate solution, more typically 100 mg to 700 mg per liter of aqueous neutral to mildly alkaline metal bicarbonate solution, even more typically 200 mg to 600 mg per liter of aqueous neutral to mildly alkaline metal bicarbonate solution, most typically 300 mg to 500 mg per liter of aqueous neutral to mildly alkaline metal bicarbonate solution, even most typically 500 mg per liter of aqueous neutral to mildly alkaline metal bicarbonate solution. The additives may also be chlorides and other appropriate salts of magnesium, sodium, potassium, calcium and lithium, such as carbonates or hydroxides or sulfates, with or without the addition of sodium bicarbonate. For example, magnesium sulfate, magnesium chloride or other soluble salts of magnesium. Further additives may include potassium bicarbonate, calcium bicarbonate or lithium bicarbonate. Generally calcium bicarbonate is prepared by adding carbonic acid or carbonated water or hydrated carbon dioxide or carbon dioxide gas to a mixture of calcium carbonate in water. Generally lithium bicarbonate is prepared by adding carbonic acid and/or carbonated water and/or hydrated carbon dioxide and/or carbon dioxide gas and/or solid carbon dioxide to a mixture of lithium carbonate in water.
The aqueous neutral to mildly alkaline metal bicarbonate solution may further include a stabilising agent. The stabilising agent may also be a pH adjusting agent. Typically the stabilising agent is a gaseous phase, for example carbon dioxide gas, which maintains and/or stabilises the solution at a pH of 7 to 9 and at a temperature of 0 to 55xc2x0 C. more typically 0 to 25xc2x0 C.
Generally once the solution is prepared, the solution may be stored under a blanket of carbon dioxide gas or a mixture of carbon dioxide gas and a nondeleterious inert gas, for example, argon, helium, air, oxygen and/or nitrogen wherein the amount of carbon dioxide present in the inert gas is sufficient to maintain the solution at a pH of 7 to 9 and at a temperature of 0 to 25xc2x0 C. and to prevent the metal bicarbonate from forming insoluble compounds which can precipitate out of solution. Typically the carbon dioxide gas above the solution prevents loss of carbon dioxide from the solution. The amount of carbon dioxide in the gaseous mixture provides partial pressure on the liquid which is substantially equal to the partial pressure which is produced from equilibrium of bicarbonate in the solution at the mixing temperature.
Magnesium Bicarbonate Particularly
Typically the production of magnesium bicarbonate utilises the dissolution of magnesium carbonate by carbonic acid or hydrated carbon dioxide solutions. Ideally, the dissolution is produced within a defined range of conditionsxe2x80x94a defined range of pH values, a defined range of temperature values and a defined minimum time. For optimal biological and medical activities, and for therapeutic safety, the concentrations of the component ions are defined also.
Typically to prepare the aqueous neutral to mildly alkaline metal bicarbonate solution, crushed or powdered metal carbonate, or metal carbonate hydroxide or metal oxide, such as magnesium carbonate MgCO3, or commercial magnesium carbonate hydroxide pentahydrate (MgCO3)4.Mg(OH)2.5H2O, or other commercial magnesium carbonate hydroxides, or hydrated magnesium oxides, or magnesium oxides heated with carbon dioxide, or the calcite series or dolomite series of minerals (Mg, Ca)CO3, or limestone or dolomite rocks is mixed with water. A cloudy suspension is obtained. Sufficient carbonic acid and/or hydrated carbon dioxide and/or carbon dioxide gas and/or solid carbon dioxide is added to obtain a solution having a pH 7 to 9 or pH 7 to 8.6, more typically pH 7.5 to 8.8 or pH 7.5 to 8.5 or pH 7.8 to 8.6, pH 7.8 to 8.5, pH 7.8 to 8.4, pH 7.8 to 8.3, pH 7.8 to 8.2, pH 7.8 to 8.1, pH 7.8 to 8.0, pH 7.8 to 7.9, pH 7.9 to 8.6, pH 7.9 to 8.5, pH 7.9 to 8.4, pH 7.9 to 8.3, pH 7.9 to 8.2, pH 7.9 to 8.1, pH 7.9 to 8.0, pH 8.0 to 8.6, pH 8.0 to 8.5, pH 8.0 to 8.4, pH 8.0 to 8.3, pH 8.0 to 8.2, pH 8.0 to 8.1, pH 8.1 to 8.6, pH 8.1 to 8.5, pH 8.1 to 8.4, pH 8.1 to 8.3, pH 8.1 to 8.2, pH 8.2 to 8.6, pH 8.2 to 8.5, pH 8.2 to 8.4, pH 8.2 to 8.3, pH 8.3 to 8.6, pH 8.3 to 8.5, pH 8.3 to 8.4, pH 8.4 to 8.6, pH 8.4 to 8.5, pH 8.5 to 8.6, even more typically pH 8 to 8.6 or pH 8.2 to 8.6, most typically pH 8.3. The solution is then typically placed in a closed or sealed container at 0 to 20xc2x0 C. or 0 to 15xc2x0 C. with occasional mixing until a clear solution develops. The amount of carbonic acid and/or hydrated carbon dioxide and/or carbon dioxide gas bubbled through the solution and dissolved therein and/or solid carbon dioxide is sufficient to prevent precipitation of water insoluble metal compounds (such as magnesium or calcium carbonate). A clear solution is generally obtained in about 6 hours to 7 days, typically 12 hours to 5 days, more typically 24 hours to 5 days, most typically 24 hours to 3 days. Generally the aqueous neutral to mildly alkaline metal bicarbonate solution is prepared and stored at a temperature ranging from 0 to 55xc2x0 C., 0 to 25xc2x0 C., 0 to 20xc2x0 C., 0.5 to 25xc2x0 C., 0.5 to 20xc2x0 C., 0.5 to 15xc2x0 C., 0.5 to 10xc2x0 C., 0.5 to 9xc2x0 C., 0.5 to 8xc2x0 C., 0.5 to 7xc2x0 C., 1 to 20xc2x0 C., 1 to 15xc2x0 C., 1 to 10xc2x0 C., 1.5 to 20xc2x0 C., 1.5 to 15xc2x0 C., 1.5 to 10xc2x0 C., 2 to 20xc2x0 C., 2 to 15xc2x0 C., 2 to 10xc2x0 C., 3 to 20xc2x0 C., 3 to 15xc2x0 C., 4 to 20xc2x0 C., 4 to 15xc2x0 C., 4 to 10xc2x0 C., 5 to 20xc2x0 C., 5 to 15xc2x0 C., 6 to 20xc2x0 C., 6 to 15xc2x0 C., 6 to 10xc2x0 C., 7 to 20xc2x0 C., 7 to 15xc2x0 C., 7 to 10xc2x0 C., 8 to 20xc2x0 C., 8 to 15xc2x0 C., 8 to 10xc2x0 C., 9 to 20xc2x0 C., 9 to 15xc2x0 C., 9 to 10xc2x0 C., 10 to 15xc2x0 C., typically 0 to 15xc2x0 C., more typically 0 to 10xc2x0 C., even more typically 3xc2x0 C. to 10xc2x0 C., most typically 5xc2x0 C. to 10xc2x0 C. and even most typically 5xc2x0 C. Alternatively the crushed or powdered metal carbonate, or metal carbonate hydroxide or metal oxide or mixture thereof is added to an aqueous solution of the carbonic acid and/or hydrated carbon dioxide and/or to an aqueous solution through which carbon dioxide gas is bubbled and/or solid carbon dioxide has been added. The amount of carbonic acid and/or hydrated carbon dioxide and/or carbon dioxide gas bubbled through the solution and dissolved therein and/or solid carbon dioxide is sufficient to prevent precipitation of water insoluble metal compounds (such as magnesium or calcium carbonate).
Typically one liter of water is placed in a container and sufficient carbonic acid and/or carbonated water and/or hydrated carbon dioxide and/or carbon dioxide gas and/or solid carbon dioxide is added to produce a pH value of approximately pH 5.2. (In practice, approximately 40 to 45 mL of chilled (5xc2x0 C.) carbonated mineral water is used depending on the initial pH of the water). The container is sealed and the contents are mixed. 485 mg magnesium carbonate hydroxide pentahydrate powder (MgCO3)4.Mg(OH)2.5H2O, molecular weight 485 is added. The container is again sealed and the contents are mixed.
The container is stored at a temperature of 0 to 10xc2x0 C. and the contents mixed regularly. Sufficient time is allowed for a clear solution of magnesium bicarbonate to develop at a range of pH 8.0 to pH 8.6, preferably pH 8.3. This takes approximately 24 to 72 hours. Alternatively the carbonic acid and/or carbonated water and/or hydrated carbon dioxide and/or carbon dioxide gas and/or solid carbon dioxide is added to the magnesium carbonate hydroxide pentahydrate powder in water. Alternatively one liter of water is placed in a container and sufficient carbonic acid and/or carbonated water and/or hydrated carbon dioxide and/or solid carbon dioxide is added to produce a pH value less than pH 5.2. (In practice, approximately 30 mL to 40 mL of chilled water is used depending on the initial pH of the water). The container is sealed and the contents are mixed. 485 mg magnesium carbonate hydroxide pentahydrate powder (MgCO3)4.Mg(OH)2.5H2O, molecular weight 485 is added. The container is again sealed and the contents are mixed. The container is stored at a temperature of 0 to 10xc2x0 C. and the contents mixed regularly. The pH of the water is then adjusted with an alkali such as sodium hydroxide or potassium hydroxide to a pH of 8 to 8.6, typically pH 8.3. Alternatively the carbonic acid or carbonated water and/or hydrated carbon dioxide and/or carbon dioxide gas and/or solid carbon dioxide is added to the magnesium carbonate hydroxide pentahydrate powder in water.
The above processes may optionally be conducted under an atmosphere of carbon dioxide or a gas comprising carbon dioxide.
Generally once the solution is prepared, it may be stored under a blanket of carbon dioxide gas to maintain the solution at a pH of 7 to 9 and at a temperature of 0 to 25xc2x0 C. Usually one liter of the magnesium bicarbonate solution prepared above contains approximately 120 mg of magnesium per liter of aqueous neutral to mildly alkaline metal bicarbonate solution and approximately 600 mg of bicarbonate. 500 mg sodium bicarbonate (or potassium bicarbonate) is added to the magnesium bicarbonate solution and mixed. The mixture is stored in a sealed container in a refrigerator. The mixture contains approximately 120 mg magnesium per liter of aqueous neutral to mildly alkaline metal bicarbonate solution, 135 mg sodium per liter of aqueous neutral to mildly alkaline metal bicarbonate solution and 950 mg bicarbonate per liter of aqueous neutral to mildly alkaline metal bicarbonate solution.
Generally the aqueous neutral to mildly alkaline metal bicarbonate solution of the invention is administered or consumed orally. Typically the solution is an orally drinkable solution. Typically the solution is a therapeutic orally drinkable solution. Alternatively a gelling agent may added to the solution and the solution subjected to gelling conditions to gel the solution and the resultant gel may be consumed orally. For example, the aqueous neutral to mildly alkaline metal bicarbonate solution may be prepared as a solution or an iced confectionary, such as an ice block or iced dessert, which is ingested orally. Alternatively the aqueous neutral to mildly alkaline metal bicarbonate solution may be prepared in the form of a tablet, lozenge or lolly which is ingested orally. For example, the aqueous neutral to mildly alkaline metal bicarbonate solution may be administered for metabolic acidosis or renal failure. Optionally the solution may be sterilised. Typically the aqueous neutral to mildly alkaline metal bicarbonate solution is prepared as a solution which is ingested on a regular basis hourly, daily, monthly or yearly. The amount and frequency of aqueous neutral to mildly alkaline metal bicarbonate solution administered/consumed in a day is generally sufficient so as to maintain a steady bicarbonate level in the bicarbonate concentration of a taker""s body fluids. It is preferable to avoid a rapid increase in the bicarbonate level in the bicarbonate concentration of a taker""s body fluids. The amount of aqueous neutral to mildly alkaline metal bicarbonate solution administered in a day ranges from 250 mL to 6 liters, typically 250 mL to 5.5 liters, 250 mL to 5 liters, 250 mL to 4.5 liters, 250 mL to 4 liters, 250 mL to 3.5 liters, 250 mL to 3 liters, 500 mL to 6 liters, 500 mL to 5.5 liters, 500 mL to 5 liters, 500 mL to 4.5 liters, 500 mL to 4 liters, 500 mL to 3.5 liters, 500 mL to 3 liters, more typically 1 liter to 6 liters, 1 liter to 5.5 liters, 1 liter to 5 liters, 1 liter to 4.5 liters, 1 liter to 4 liters, 1 liter to 3.5 liters, even more typically 1 liter to 3 liters, 1.5 liters to 6 liters, 1.5 liters to 5.5 liters, 1.5 liters to 5 liters, 1.5 liters to 4.5 liters, 1.5 liters to 4 liters, 1.5 liters to 3.5 liters, 1.8 liters to 3.3 liters, 1.8 to 2.8 liters, 1.8 to 2.5 liters, 1.8 to 2.3 liters, 1.8 to 2.0 liters, most typically 2 to 3 liters, typically 2.3 to 2.8 liters, more typically 2.3 to 2.6 liters, usually 2.1 to 3 liters. The aqueous neutral to mildly alkaline metal bicarbonate solution may be administered on a full or empty stomach, typically the aqueous neutral to mildly alkaline metal bicarbonate solution is administered on an empty stomach. Usually 1.5 to 3.5 liters, typically 1.8 to 3 liters, more typically 1.5 to 2.4 liters, even more typically 1.8 to 2.1 liters and usually between 1.8 and 2.7 liters of aqueous neutral to mildly alkaline metal bicarbonate solution is ingested, administered or consumed on an empty stomach by a mammal (typically a human) in equal or non equal volume amounts (100 mL-1000 mL, 200-800 mL, 250-750 mL, 275-700 mL, 300-650 mL, 350-600 mL, 400-550 mL, 450-500 mL, typically about 300-400 mL, more typically about 375 mL volume amounts a number of times (typically at set times) each day for the required number of times per day to drink the desired daily amount of the solution). For example if 1800 mL per day is to be consumed then a user may drink six 300 mL amounts of the solution every 2 to 2.5 hours throughout the day. The oral consumption of the solution three or more times at roughly equally spaced apart intervals throughout the day is more desirable than consuming the solution in one or two lots throughout the day. The idea of taking the solution is to take it regularly throughout the day so that a simulated continuous oral intake or a close to continuous regular oral intake of the solution occurs. Thus depending on the condition and the subject one suitable administration/consumption regime could be nine by 200 mL amounts of the solution, each 200 mL amount being orally administered/consumed about every 1.5-1.75 hours to provide a total daily intake of 1800 mL. Alternatively, once again depending on the condition and the subject one suitable administration/consumption regime could be nine by 300 mL amounts of the solution, each 300 mL amount being orally administered/consumed about every 1.5-1.75 hours to provide a total daily intake of 2700 mL. Alternatively, once again depending on the condition and the subject one suitable administration/consumption regime could be nine by 350 mL amounts of the solution, each 350 mL amount being orally administered/consumed about every 1.5-1.75 hours to provide a total daily intake of 3150 mL. Typically the solution is administered/consumed 3 to 30, 3-25, 3-20, 3-15, 3-12, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4-30, 4-25, 4-20, 4-15, 4-12, 4-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-30, 5-25, 5-20, 5-15, 5-12, 5-11, 5-10, 5-9, 5-8, 5-7, 5-6, 6-30, 6-25, 6-20, 6-15, 6-12, 6-11, 6-10, 6-9, 6-8, 6-7, 7-30, 7-25, 7-20, 7-15, 7-12, 7-11, 7-10, 7-9, 7-8, 8-30, 8-25, 8-20, 8-15, 8-12, 8-11, 8-10, 8-9 times per day at regular or irregular intervals or a mixture of both regular and irregular intervals, throughout each day. Typically the solution is administered/consumed every 0.3-10, 0.3-8, 0.3-7, 0.3-6, 0.3-5, 0.3-4.5, 0.3-4, 0.3-3.5, 0.3-3, 0.3-2.5, 0.3-2, 0.3-1.5, 0.3-1, 0.3-0.75, 0.3-0.5 hours/day when the subject is awake. More typically the solution is administered/consumed every 0.5-8, 0.5-7, 0.5-6, 0.5-5, 0.5-4.5, 0.5-4, 0.5-3.5, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1, 0.5-0.8, 0.5-0.75 hours/day when the subject is awake. Where possible the solution is consumed/administered on an empty (e.g. before eating). The solution may be administered according to these latter dosages over short (for example 1 to 60 days, 10 to 40 days, 3 months to 6 months, 1 day to 6 months) or long (for example 6 months to 10 years or more, 9 months to 1 8 months, 1 year to 3 years, 1 year to 5 years, 2 to 6 years) periods as required. Usually the amount of aqueous neutral to mildly alkaline metal bicarbonate solution administered to a mammal is 5 to 100 mL per Kg, more usual 10 to 50 mL per Kg, most usual 14 to 29 mL per Kg or 25 to 43 mL per Kg.
The solution may include other additives such as sweeteners, preservatives, flavourings and other suitable additives. Examples of suitable sweetners include sucrose, lactose, glucose, aspartame or saccharine. Examples of suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring. Examples of suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite.
Typically the aqueous neutral to mildly alkaline metal bicarbonate solution is orally administered/consumed on an empty stomach. Usually consumption in this manner avoids the mixing of bicarbonate anions with stomach acid which may result in the loss of bicarbonate. Usually the aqueous neutral to mildly alkaline metal bicarbonate solution is consumed in small amounts a number of times through a day typically at set times each day to avoid a rapid increase in the bicarbonate concentration of body fluids. Usually the amount of aqueous neutral to mildly alkaline metal bicarbonate solution consumed at commencement is 500 mL per day and is increased by increments over a period of one month to the maximum consumption. This start-up schedule generally avoids any gastrointestinal side effects due to the smooth muscle relaxation properties of magnesium.
The aqueous neutral to very mildly alkaline metal bicarbonate solution of the invention may be administered intravenously (e.g. by discrete injection, semi continuous injection or drip feed or continuous injection or drip feed) or by other parenteral routes. Another embodiment of the invention is directed to a pharmaceutical composition comprising the solution of the first or eleventh embodiments together with one or more pharmaceutically acceptable carriers, diluents, adjuvants and/or excipients. Typically the pharmaceutical composition is suitable for oral or parenteral administration. Another embodiment of the invention is directed to a veterinary composition comprising the solution of the first or eleventh embodiments together with one or more veterinarily acceptable carriers, diluents, adjuvants and/or excipients. Typically the veterinary composition is suitable for oral or parenteral administration. The amount and frequency of aqueous neutral to mildly alkaline metal bicarbonate solution administered/consumed in a day is generally sufficient so as to maintain a steady bicarbonate level in the bicarbonate concentration of a taker""s body fluids. It is preferable to avoid a rapid increase in the bicarbonate level in the bicarbonate concentration of a talker""s body fluids. For parenteral administration, the solution is generally sterile. Suitable mono-toxic parenterally acceptable diluents or solvents include water, Ringer""s solution, isotonic salt solution, 1,3-butanediol, ethanol, propylene glycol or polyethylene glycols in mixtures with water. Aqueous solutions or suspensions may further comprise one or more buffering agents. Suitable buffering agents include sodium borate, sodium acetate, sodium citrate, or sodium tartrate, for example. Typically the solution is administered on a regular basis throughout a day to a patient requiring treatment. For example a patient may be parenterally administered the solution by way of a continuous drip feed or alternatively by way of a number of injections of the solution throughout a day (e.g. every 0.5-8 hours, more typically every 1-4 hours). The treatment is generally continued as long as required to alleviate the patient""s symptons to a satisfactory level. For concentration of metal bicarbonate in the compositions, frequency of administration and amount administered see discussion under oral administration.